Dose related effects of salbutamol and ipratropium bromide on airway calibre and reactivity in subjects with asthma.

The relationship between change in airway calibre and change in airway reactivity after administration of bronchodilator drugs has been investigated by comparing the effect of increasing doses of inhaled salbutamol and ipratropium bromide on the forced expiratory volume in one second (FEV1), specific airways conductance (sGaw), and the dose of histamine causing a 20% fall in FEV1 (PD20) in six subjects with mild asthma. On each of 10 occasions measurements were made of baseline FEV1, sGaw, and PD20 after 15 minutes' rest, and followed one hour later, when the FEV1 had returned to baseline, by a single nebulised dose of salbutamol (placebo, 5, 30, 200 and 1000 micrograms) or ipratropium (placebo, 5, 30, 200 and 1000 micrograms) given in random order. Measurements of FEV1, sGaw, and PD20 were repeated 15 minutes after salbutamol and 40 minutes after ipratropium. Salbutamol and ipratropium caused a similar dose related increase in FEV1 and sGaw, with a mean increase after the highest doses of 0.76 and 0.69 litres for FEV1 and 1.15 and 0.96 s-1 kPa-1 for sGaw. Salbutamol also caused a dose related increase in PD20 to a maximum of 2.87 (95% confidence interval 2.18-3.55) doubling doses of histamine after the 1000 micrograms dose, but ipratropium bromide caused no significant change in PD20 (maximum increase 0.24 doubling doses, 95% confidence interval -0.73 to 1.22). Thus bronchodilatation after salbutamol was associated with a significantly greater change in airway reactivity than a similar amount of bronchodilatation after ipratropium bromide. This study shows that the relation between change in airway reactivity and bronchodilatation is different for two drugs with different mechanisms of action, suggesting that change in airway calibre is not a major determinant of change in airway reactivity with bronchodilator drugs.     

Characterisation of bronchoconstrictor responses to sodium metabisulphite aerosol in atopic subjects with and without asthma.

Inhalation of sodium metabisulphite is thought to induce bronchoconstriction by release of sulphur dioxide. We sought to establish the reproducibility of the airway response to inhaled sodium metabisulphite given in increasing doubling concentrations (0.3 to 160 mg/ml) to 13 asthmatic and five atopic non-asthmatic subjects and the contribution of cholinergic mechanisms to this response. In 15 of the 18 subjects bronchoconstriction was sufficient to allow calculation of the dose of metabisulphite causing a 20% reduction in the forced expiratory volume in one second (FEV1) from baseline values (PD20 metabisulphite). The 95% confidence limit for the difference between this and a second PD20 metabisulphite determined 2-14 days later was 2.5 doubling doses. The difference between repeat PD20 metabisulphite measurements was unrelated to the number of days between challenges or change in baseline FEV1. Ten subjects returned for a third study 3-120 days after the second challenge; variability in PD20 metabisulphite did not differ from that seen between the first and second challenges. PD20 methacholine was determined between the two metabisulphite challenges and found to correlate with PD20 metabisulphite (r = 0.71). Inhaled ipratropium bromide 200 micrograms given in a randomised, placebo controlled, crossover study to 10 subjects increased PD20 methacholine 42 fold but had no significant effect on the response to metabisulphite. A single inhalation of the PD20 metabisulphite in five subjects induced maximal bronchoconstriction 2-3 minutes after inhalation, with a plateau in FEV1 lasting a further four minutes before recovery. A further single inhalation of the same PD20 dose 43 minutes later produced a 27% (SEM 4%) smaller fall in FEV1 than the first inhalation. These results show that metabisulphite PD20 values measured over days and weeks show similar reproducibility to those reported for histamine inhalation and that PD20 metabisulphite correlates with methacholine responsiveness. Most of the bronchoconstriction is not inhibited by antimuscarinic agents; the underlying mechanisms require further investigation.     

Effect of inhaled prostaglandin E2 on bronchial reactivity to sodium metabisulphite and methacholine in patients with asthma.

Inhaled frusemide protects against the bronchoconstrictor response to a wide range of stimuli that cause bronchoconstriction by indirect mechanisms. One possible explanation for this protection relates to the known ability of frusemide to enhance synthesis of prostaglandin E2 (PGE2). Studies in vitro suggest that PGE2 might protect against indirectly acting bronchoconstrictor challenges rather than those that act directly on airway smooth muscle, though little is known about the effects of PGE2 in vivo. The effect of inhaled PGE2 on the bronchoconstrictor response to inhaled sodium metabisulphite (a stimulus with an indirect action) and methacholine (which acts directly on airway smooth muscle) was studied in nine patients with asthma. Subjects were studied on four days, inhaling PGE2 (100 micrograms) or placebo in a double blind fashion followed immediately by a cumulative dose challenge with sodium metabisulphite or methacholine. The response to the constrictor stimuli was measured as the provocative dose causing a 20% fall in FEV1 (PD20). There was no significant change in FEV1 after inhaled PGE2 compared with placebo, nor any significant change in the response to methacholine; the geometric mean methacholine PD20 was 0.9 mumol after PGE2 and 0.56 mumol after placebo (mean difference 0.7 (95% confidence limits--0.1, 1.5) doubling doses). PGE2, however, protected against sodium metabisulphite, the geometric mean sodium metabisulphite PD20 being 11.8 mumol after PGE2 and 1.8 mumol after placebo (mean difference 2.5 (95% CL 1.9, 3.1) doubling doses). PGE2 conferred significantly greater protection against sodium metabisulphite than methacholine (mean difference 1.8 (95% CL 0.8, 2.8) doubling doses). This suggests that PGE2, like frusemide, has an inhibitory effect on pathways relevant to the bronchoconstriction induced by sodium metabisulphite, with little or no effect on those relevant to methacholine.     

Effect of allergen challenge on airway responsiveness to histamine and sodium metabisulphite in mild asthma.

BACKGROUND: Airway responsiveness to histamine and methacholine, direct smooth muscle spasmogens, is increased following inhalation of allergen. Although the aetiology of this phenomenon is unclear, increased cellular or neural activity may be involved since allergen also induces increases in airway responsiveness to the mast cell stimulus adenosine-5'-monophosphate (AMP) and the neural stimulus bradykinin. METHODS: To explore this further, the airway responsiveness to sodium metabisulphite (MBS), an indirect neural stimulus with similar characteristics to bradykinin, was compared in 18 mild steroid-naive asthmatic subjects with the airway responsiveness to histamine before and after allergen challenge with extracts of house dust mite, grass pollen, or cat. All subjects inhaled doubling increments of histamine and MBS until the concentration provoking a 20% fall in forced expiratory volume in one second (PC20) was reached before and three hours after allergen challenge. Twelve of the subjects had additional challenges at 24 hours after the allergen. RESULTS: Following allergen challenge all subjects showed an early response and 14 also had a late asthmatic response. For histamine there was a significant increase in airway responsiveness at both three and 24 hours compared with values before the allergen (0.89 (0.25) and 1.53 (0.52) doubling dose changes, respectively). In contrast, airway responsiveness to MBS was unaltered by allergen challenge (0.29 (0.27) and -0.33 (0.28) doubling dose changes compared with pre-allergen values at three and 24 hours, respectively). CONCLUSION: These data suggest that activation of airway sensory nerves is unlikely to contribute to the increase in airway responsiveness following inhalation of allergen. The previously observed allergen induced increase in airway responsiveness to bradykinin and AMP may involve non-neural pathways.     

Comparison of three inhaled non-steroidal anti-inflammatory drugs on the airway response to sodium metabisulphite and adenosine 5'-monophosphate challenge in asthma.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are used to assess the role of prostaglandins in asthma but their effects on bronchoconstrictor challenges have been inconsistent. The effects of three nebulised nonsteroidal anti-inflammatory drugs on the airway response to inhaled sodium metabisulphite (MBS) and adenosine 5'-monophosphate (AMP) were compared in the same asthmatic subjects to see whether contractile prostaglandins were involved in MBS or AMP induced bronchoconstriction. A possible protective effect of the osmolarity or pH of the inhaled solutions was also assessed. METHODS: Two double blind placebo controlled studies were carried out. In study 1, 15 non-aspirin sensitive patients with mild asthma attended on four occasions and inhaled 5 ml of lysine aspirin (L-aspirin) 900 mg, indomethacin 50 mg, sodium salicylate 800 mg, or saline 20 minutes before an inhaled MBS challenge. On four further occasions 14 of the patients inhaled the same solutions followed by an inhaled AMP challenge. In study 2, 10 of the patients attended on four additional occasions and inhaled 5 ml of 0.9%, 3%, 10%, or 9.5% saline with indomethacin 50 mg 20 minutes before an inhaled MBS challenge. RESULTS: In study 1 inhaled lysine aspirin had a similar effect on MBS and AMP induced bronchoconstriction, increasing the provocative dose causing a 20% fall in FEV1 (PD20) by 1.29 (95% CI 0.54 to 2.03) and 1.23 (95% CI 0.53 to 1.93) doubling doses, respectively. Indomethacin increased the MBS PD20 and AMP PD20 by 0.64 (95% CI -0.1 to 1.38) and 0.99 (95% CI 0.29 to 1.69) doubling doses, respectively. Sodium salicylate had no significant effect on either challenge. The two solutions causing most inhibition were the most acidic and the most alkaline. In study 2 inhaled 9.5% saline with indomethacin (osmolarity 3005 mOsm/kg) increased the MBS PD20 by 1.1 doubling doses (95% CI 0.2 to 2.0) compared with only 0.09 (95% CI -0.83 to 1.0) and 0.04 (95% CI -0.88 to 0.95) doubling doses with 3% saline (918 mOsm/kg) and 10% saline (2994 mOsm/ kg), respectively. CONCLUSIONS: Inhaled L-aspirin and indomethacin have broadly similar protective effects against MBS and AMP induced bronchoconstriction in the doses given, although the effect of indomethacin on MBS was not quite statistically significant. The osmolarity and pH of the solutions did not appear to be important determinants of the response. The effect of L-aspirin and indomethacin is likely to be the result of cyclooxygenase inhibition reducing the production of contractile prostaglandins during MBS and AMP challenge.     

Occupational asthma caused by dry metabisulphite.

A case is described of occupational asthma in a worker with no previous history of asthma who sprinkled dried metabisulphite powder onto potatoes and developed work-related symptoms. Occupational asthma was confirmed by specific inhalation challenges.     

Cross refractoriness between sodium metabisulphite and exercise induced asthma.

BACKGROUND--Exercise and inhaled sodium metabisulphite are thought to cause bronchoconstriction in asthma through different mechanisms. The response to both stimuli becomes refractory with repeat challenge. The mechanism of refractoriness is unclear, although depletion of mast cell derived mediators or neurotransmitters has been suggested. Recent studies suggest a common mechanism involving release of inhibitory prostaglandins. If this is true, exercise and sodium metabisulphite induced bronchoconstriction should show cross refractoriness. METHODS--Thirteen subjects with mild asthma and previously established exercise and sodium metabisulphite induced bronchoconstriction performed two sodium metabisulphite challenges (giving a single dose previously shown to cause a 20% fall in FEV1) on one study day, and two exercise tests on another. The second challenge proceeded after recovery (FEV1 > 95% baseline) from the first. Subjects then attended on two further occasions when an exercise test was performed after sodium metabisulphite and a sodium metabisulphite challenge after exercise. RESULTS--When expressed as the percentage reduction in the area under the change in percentage FEV1 curve over 20 minutes (AUC) the response to exercise was reduced by a mean 62.3% (95% CI 46.5% to 78.1%) following a first exercise challenge, and by 50.7% (95% CI 27.8% to 73.6%) following a sodium metabisulphite challenge. The response to a sodium metabisulphite challenge was reduced by a mean of 80.2% (95% CI 68.9% to 91.5%) when it followed a sodium metabisulphite challenge, and by 37.3% (95% CI 15.1% to 59.5%) following an exercise challenge. CONCLUSION--This study shows some cross refractoriness between exercise and sodium metabisulphite induced bronchoconstriction, in keeping with a partially shared mechanism of refractoriness.     

Effect of azelastine on sulphur dioxide induced impairment of ciliary motility in airway epithelium.

OBJECTIVE--The effect of azelastine on airway mucociliary transport function was studied by measuring ciliary motility of human bronchial epithelium in vitro with a photoelectric method. METHOD--Bronchial epithelial cells were obtained by fibreoptic bronchoscopy, mounted in a Rose chamber, and perfused with Krebs-Henseleit solution. The preparations were placed on a microscope stage equipped with an illuminator, and the variations of light intensity caused by ciliary beating were detected by a photometer. RESULTS--The addition of azelastine to the perfusate increased ciliary beat frequency (CBF) in a dose dependent manner without ciliary discoordination. The mean (SE) maximal increase from the baseline value and the concentration required to produce a half maximal effect were 27.0 (4.2)% and 9.2 x 10(-6) mol/l, respectively. Exposure of the cells to the perfusate containing 3 ppm sulphur dioxide rapidly decreased CBF by 59.2 (5.0)%, and was accompanied by a reduction in intracellular cyclic AMP levels from 38.1 (4.3) to 10.1 (2.4) pmol/mg protein. This effect was prevented by pretreatment of cells with azelastine in a dose dependent manner. CONCLUSIONS--Azelastine not only stimulates ciliary motility of airway epithelium and hence mucociliary transport function, but may also protect against sulphur dioxide induced ciliary dysfunction, probably by inhibiting intracellular cyclic AMP loss.     

Comparison of airway reactivity induced by histamine, methacholine, and isocapnic hyperventilation in normal and asthmatic subjects

In an investigation of a rapid screening test for airway reactivity using isocapnic hyperventilation with room air and cold air the results of this test were compared with the airway response to histamine and methacholine challenge. Twelve non-atopic, non-smoking normal subjects and 11 subjects with stable asthma who had an FEV1 above 74% of the predicted value were studied. In the normal subjects isocapnic hyperventilation with room air (75 l/min; 22 degrees C (SEM 0.2 degrees); 10 mg H2O/l air) and isocapnic hyperventilation with cold air (77 l/min; -10 degrees C (0.9 degrees); 2.4 mg H2O/l air) produced no significant change in FEV1. In the asthmatic subjects, hyperventilation with room air (71 l/min; 22 degrees C (0.8 degrees); 10 mg H2O/l air) caused a mean fall in FEV1 of 11.7%; cold air hyperventilation (70 l/min; -10 degrees C (0.9 degrees); 2.4 mg H2O/l air) caused a mean fall in FEV1 of 20.4%. Cold air hyperventilation produced greater separation between normal and asthmatic subjects than room air. The provocative concentration of histamine required to reduce the FEV1 by 20% (PC20) correlated closely with the PC20 for methacholine (r = 0.95; p less than 0.001). Both tests separated normal from asthmatic subjects. PC20 for both histamine and methacholine correlated with the fall in FEV1 after cold air hyperventilation (r = 0.93, p less than 0.001; r = 0.87, p less than 0.001 respectively). We conclude that the results of a rapid screening test based on hyperventilation with cold air correlate well with a standard pharmacological challenge.     

Temporal association between hospital admissions for asthma in Birmingham and ambient levels of sulphur dioxide and smoke.

BACKGROUND--A study was performed to determine whether daily and weekly variations in the levels of smoke and sulphur dioxide (SO2) in Birmingham are related to hospital admissions for asthma and acute respiratory diseases. METHODS--Daily numbers of hospital admissions for asthma (ICD code 493) and acute respiratory conditions (ICD 466, 480-486, 490-496) for residents of Birmingham between 1988 and 1990 were obtained from West Midlands RHA Körner inpatient data. Average daily levels of sulphur dioxide and smoke were obtained from Birmingham City Council for the same period, together with daily meteorological summaries from the Department of Geography, University of Birmingham. With the exception of one day, all air pollution measurements remained within current EC guide levels. Data were divided into seasons and the relation between hospital admissions and pollutant levels were explored by stepwise least squares regression models. Meteorological variables (temperature, pressure, humidity) were entered into the model if they showed significant association with hospital admissions during the season in question. Analysis was undertaken for daily (same day and lagged by two days) and weekly pollutant levels. Admissions were lagged behind pollution levels to allow for delayed effects of pollutants. RESULTS--The mean daily level of smoke was 12.7 micrograms/m3 and of SO2 was 39.1 micrograms/m3, with maxima of 188.3 micrograms/m3 and 126.3 micrograms/m3, respectively. Significant associations were found between hospital admissions for respiratory disease lagged by two days, and smoke and SO2 levels during winter. Associations between admissions for asthma and smoke and SO2 levels were significant at the 5% level. These were independent of temperature, pressure, and humidity. Stepwise regression including both pollutants showed that smoke, but not SO2, was a significant independent predictor of hospital admissions for both asthma and all respiratory conditions. During winter a rise of 100 micrograms/m3 smoke might result in five (95% CI 0.6 to 9) more asthma admissions and 21.5 (95% CI 10 to 33) more acute respiratory admissions each day in Birmingham. A 100 micrograms/m3 rise in SO2 might result in four (0 to 7) more asthma admissions and 15.5 (6 to 25) more respiratory admissions each day. Independent associations were also found between weekly mean smoke and SO2 levels and all respiratory admissions during autumn and winter. During summer, daily mean smoke and SO2 levels were significantly associated with non-lagged daily admissions for all respiratory diseases (p < 0.02). There was no association between air pollution and hospital admissions during spring. CONCLUSIONS--Daily variations in smoke and SO2 levels are significantly associated with hospital admissions for asthma and respiratory disease during winter in Birmingham at levels of air pollutants within the EC guide levels. This association was independent of potential confounding effects of weather (temperature, pressure, humidity) and suggests that current levels of air pollution can still produce significant health effects.     

Comparison of airway immunopathology of eosinophilic bronchitis and asthma

BACKGROUND: Eosinophilic bronchitis is a condition characterised by a corticosteroid responsive cough, sputum eosinophilia, and normal tests of variable airflow obstruction and airway responsiveness. We performed a detailed comparative immunopathological study to test the hypothesis that the different airway function in patients with eosinophilic bronchitis and asthma reflects differences in the nature of the lower airway inflammatory response. METHODS: Exhaled nitric oxide was measured and induced sputum, bronchoscopy, bronchial wash (BW), bronchoalveolar lavage (BAL), and bronchial biopsy were performed in 16 subjects with eosinophilic bronchitis, 15 with asthma, and 14 normal controls. RESULTS: Both eosinophilic bronchitis and asthma were characterised by an induced sputum, BW and BAL eosinophilia, an increased number of epithelial and subepithelial eosinophils, and increased reticular basement membrane thickness. The median concentration of exhaled nitric oxide was higher in those with eosinophilic bronchitis (12 ppb) or asthma (8.5 ppb) than normal controls (2 ppb) (95% CI of the difference 5 to 16, p<0.0001 and 2 to 11.3, p=0.004, respectively). There were no group differences in epithelial integrity or the number of subepithelial T lymphocytes, mast cells or macrophages. CONCLUSION: With the exception of our previously reported association of smooth muscle mast cell infiltration with asthma, the immunopathology of eosinophilic bronchitis and asthma are similar which suggests that eosinophilic airway inflammation, increased exhaled nitric oxide, and increased basement membrane thickening are regulated independently of airway hyperresponsiveness.     

Effects of sodium metabisulphite on guinea pig contractile airway smooth muscle responses in vitro.

BACKGROUND--Sodium metabisulphite (MBS) is known to induce bronchoconstriction in asthmatic patients. The effects of MBS on guinea pig airway smooth muscle and on neurally mediated contraction in vitro have been examined. METHODS--Tracheal and bronchial airway segments were placed in oxygenated buffer solution and electrical field stimulation was performed in the presence of indomethacin (10(-5) M) and propranolol (10(-6) M) for the measurement of isometric tension. Atropine (10(-6) M) was added to bronchial tissues. RESULTS--Concentrations of MBS up to 10(-3) M had no direct effect on airway smooth muscle contraction and did not alter either tracheal smooth muscle contraction induced by electrical field stimulation at all frequencies or acetylcholine-induced tracheal smooth muscle contraction. There was a similar response in the absence of epithelium, except for potentiation of the response induced by electrical field stimulation at 0.5 Hz (24 (10)% increase). However, MBS (10(-5), 10(-6) and 10(-7) M) augmented neurally-mediated non-adrenergic non-cholinergic contractile responses in the bronchi (13.3 (3.2)%, 23.8 (9.6)%, and 6.4 (1.6)%, respectively). MBS had no effect on the contractile response induced by substance P, but at higher concentrations (10(-3) M and 10(-4) M) it caused a time-dependent attenuation of responses induced by either electrical field stimulation or exogenously applied acetylcholine or substance P. CONCLUSIONS--MBS had no direct contractile responses but enhanced bronchoconstriction induced by activation of non-cholinergic neural pathways in the bronchus, probably through increased release of neuropeptides. At high concentrations MBS inhibited contractile responses initiated by receptor or neural stimulation.     

Differential effects of propofol on cerebrovascular carbon dioxide reactivity in elderly versus young subjects

STUDY OBJECTIVE: To examine the age-related difference between elderly and young patients in the effect of propofol on cerebrovascular carbon dioxide (CO(2)) reactivity. DESIGN: Prospective controlled study. SETTING: University hospital. PATIENTS: Elderly (older than 70 years, n = 13) and young patients (younger than 25 years, n = 13) scheduled for elective orthopedic surgery. INTERVENTIONS: After induction of anesthesia, a 2.5-MHz pulsed transcranial Doppler probe was attached to the patient's head at the right temporal window, from which mean blood flow velocity of the middle cerebral artery was measured continuously. MEASUREMENTS: After obtaining baseline values of velocity of the middle cerebral artery, arterial blood gases, and cardiovascular hemodynamics, end-tidal CO(2) was decreased by increasing the ventilatory frequency by 2 to 5 breaths per minute. Measurements were repeated when end-tidal CO(2) decreased and remained stable for 5 to 10 minutes. Cerebrovascular CO(2) reactivity, at propofol doses of 5 and 10 mg/kg/h, was measured. MAIN RESULTS: No significant differences were observed between the 2 groups in baseline absolute and relative CO(2) reactivity. However, there were significant differences between the 2 groups in absolute or relative CO(2) reactivity at a propofol dosage of 5 mg/kg/h. (Absolute CO(2) reactivity in young patients: 2.1 +/- 0.8 cm/s/mm Hg; elderly: 1.6 +/- 0.4* cm/s/mm Hg. Relative CO(2) reactivity in young patients: 7.4% +/- 1.6%/mm Hg; in the elderly: 6.5% +/- 0.9%*/mm Hg; unpaired t test, *P < .05). In contrast, there were no significant differences between the 2 groups in terms of absolute or relative CO(2) reactivity at a propofol dosage of 10 mg/kg/h. CONCLUSIONS: Cerebrovascular CO(2) reactivity in elderly patients was lower than that in young patients at a propofol dosage of 5 mg/kg/h.     

Mechanisms of sulphur dioxide induced bronchoconstriction in normal and asthmatic man.

We have examined the inhibitory effect of atropine and sodium cromoglycate (SCG) on the bronchial response to sulphur dioxide (SO2) in groups of normal and asthmatic subjects. Eleven normal subjects were premedicated with propranolol (100 mg orally) one hour before each experiment. After baseline measurements of specific airways conductance (sGaw) the subject inhaled an aerosol from a Wright nebuliser for five minutes. In separate experiments this contained water (control), atropine methonitrate (0 . 2%), or SCG (1%). Fifteen minutes later sGaw was remeasured and the subject then breathed SO2 (8 ppm) for three minutes through the mouth. Specific airways conductance was measured for the duration of the subsequent response. Intervals between experiments on any one subject were one week or more. After control SO2 inhalation sGaw decreased in all subjects (mean 34 +/- 17 (SD)%). Atropine and SCG significantly inhibited the SO2 response (p less than 0 . 01 for both). After atropine the mean decrease in sGaw was 13 +/- 24%; after SCG 16 +/- 12% (range -3- + 55%). With atropine the degree of inhibition was inversely related to the subject's responsiveness to the control SO2 inhalation (r = 0 . 75; p less than 0 . 01). In four asthmatics (without beta-blockade and with lower SO2 exposure) atropine did not inhibit the SO2 response; SCG had a similar effect to that seen in normal subjects. Therefore, vagal efferent mechanisms are involved in the bronchial response to SO2 in normal subjects, but the lack of inhibition caused by atropine in hyperreactive normal and asthmatic subjects suggests that vagal mechanisms are not important in the causation of hyperreactivity to SO2. The mechanism of inhibition with SCG is unknown.     

Inhibition of sodium metabisulphite induced bronchoconstriction by frusemide in asthma: role of cyclooxygenase products.

BACKGROUND--Inhaled frusemide inhibits airway responses to sodium metabisulphite and other indirect bronchial challenges in asthma by undetermined mechanisms which may relate to its ability to stimulate prostaglandin release. Inhalation of sodium metabisulphite provokes indirect bronchoconstriction, possibly by activating sensory nerves. To investigate the role of cyclooxygenase products in the airway actions of frusemide and sodium metabisulphite, the effects of a potent cyclooxygenase inhibitor, flurbiprofen, alone and in combination with frusemide were investigated against airway responsiveness to sodium metabisulphite. METHODS--In a double blind double placebo controlled study, 12 mild asthmatic subjects attended on four occasions to undergo three inhalation challenges with sodium metabisulphite. A baseline challenge was performed one hour before oral intake of flurbiprofen 200 mg or matched placebo, and two hours before inhalation of frusemide 40 mg or matched placebo. A second challenge was performed immediately after inhalation of frusemide (two hours after flurbiprofen) with a further challenge three hours later. The log concentration provoking a 20% fall in FEV1 (log PC20) was used to assess airway responsiveness to sodium metabisulphite. RESULTS--Frusemide caused an immediate 1.9 doubling dose protection and a lesser 0.7 doubling dose protection at three hours. This protection was enhanced by flurbiprofen at both time points to 2.7 (early) and 1.9 (late) doubling doses. In addition, flurbiprofen alone significantly reduced airway responsiveness to sodium metabisulphite by 1.1 doubling doses at both two and five hours. CONCLUSIONS--The generation of bronchoprotective prostaglandins is unlikely to underlie the inhibitory action of frusemide against airway responsiveness to sodium metabisulphite. Endogenous contractile prostaglandins within the airways may be involved in the bronchoconstrictor response to sodium metabisulphite.     

Effect of nedocromil sodium on sulphur dioxide induced bronchoconstriction.

Nedocromil sodium is a pyranoquinoline derivative that has been developed for the treatment of asthma. We report the results of a double blind randomised study of the effect of two doses of nedocromil sodium (2 and 4 mg) and matched placebo, delivered by metered dose pressurised aerosol, on bronchoconstriction induced by sulphur dioxide in six asthmatic subjects. Nedocromil sodium had no effect on baseline lung function. The magnitude of sulphur dioxide induced bronchoconstriction monitored by partial forced expiratory flow at 30% of reference vital capacity was significantly inhibited by nedocromil sodium 4 mg (p less than 0.05) but not by 2 mg. The maximum changes after placebo and after nedocromil 2 mg and 4 mg were -44.7, -32.7, and -11.8 l min-1. The area under the curve monitoring the effect over 6 minutes was significantly inhibited by both doses to the same extent, the mean changes after placebo and after nedocromil 2 mg and 4 mg being -349.3, -31.2, and 44.6 l. Dyspnoea was monitored by visual analogue scale and showed a significant reduction over 6 minutes with both doses of nedocromil. After placebo and after nedocromil 2 mg and 4 mg the mean maximum changes were 31.5, 13.7, and 15.7 mm, and the mean changes in area under the visual analogue scale-time curve were 289, 194, and 151 mm.min respectively.     

Effect of ambient levels of smoke and sulphur dioxide on the health of a national sample of 23 year old subjects in 1981.

BACKGROUND--There is concern that, despite the fall in air pollution levels since the 1950s, there may still be adverse effects at current levels. A study was carried out to investigate the association between air pollution and respiratory symptoms in 23 year old subjects in 1981. METHODS--Data on cough, phlegm, and wheeze were available on 11,552 members of the 1958 national birth cohort. Counties in the UK were ranked by annual average level of black smoke and sulphur dioxide (SO2), and then divided into five groups. The subject''s county of residence determined their categorisation of pollution exposure. The association between air pollution exposure and respiratory symptoms was examined by logistic regression, adjusting for social class, sex, and smoking. RESULTS--The ranges of the air pollution groups were 2.0-13.0, 13.1-18.7, 19.6-20.8, 21.0-25.8, and 26.1-55.1 micrograms/m3 for black smoke, and 7.0-36.4, 36.7-42.7, 43.0-50.5, 52.0-59.3, and 60.9-87.7 micrograms/m3 for SO2. The overall prevalences of cough, phlegm, wheezing since age 16, and wheezing in the past year were 13.3%, 10.3%, 9.4%, and 4.4%, respectively. Phlegm symptoms increased with increasing smoke levels with evidence of a plateau. Cough and wheeze were not associated with black smoke; no symptom was associated with SO2. In the subgroup with wheeze at ages 16-23 there was no effect of smoke level on phlegm. CONCLUSIONS--Low ambient levels of black smoke were associated with decreased prevalence of phlegm symptoms in young adults in the UK in 1981. The effect was evident below the current EC guideline of 34-51 micrograms/m3 annual black smoke. In 1991 the annual mean smoke level for each county ranged from 3.4 to 26.5 micrograms/m3, spanning all but the last exposure group used here. This is consistent with the existence of adverse and possibly chronic effects at current levels.     

The airway microvasculature and exercise induced asthma.

It has been proposed that exercise induced asthma is a result of "rapid expansion of the blood volume of peribronchial plexi" (McFadden ER, Lancet 1990;335:880-3). This hypothesis proposes that the development of exercise induced asthma depends on the thermal gradient in the airways at the end of hyperpnoea. The events that result in exercise induced asthma are vasoconstriction and airway cooling followed by reactive hyperaemia. We agree that the airway microcirculation has the potential for contributing to the pathophysiology of exercise induced asthma. We do, however, question whether reactive hyperaemia, in response to airway cooling, is the mechanism whereby hyperpnoea provokes airways obstruction in asthmatic patients. Further, we question whether vasoconstriction accompanies dry air breathing and whether an abnormal temperature gradient and rapid rewarming of the airways are prerequisites for exercise induced asthma. From published experiments we conclude that dry air breathing is associated with vasodilation and increase in airway blood flow rather than vasoconstriction and a decrease in blood flow to the airways. We propose that the stimulus for the increase in airway blood flow is an increase in osmolarity of the airway submucosa. This osmotic change is caused by the movement of water to the airway lumen in response to evaporative water loss during hyperpnoea. The increase in airway blood flow may occur directly or indirectly by the osmotic release of mediators. Exercise induced asthma is most likely to be due to the contraction of bronchial smooth muscle caused by the same mediators. Whether it is enhanced or inhibited by alterations in airway blood flow is not yet established in man.